Isonitrile compounds and derivatives thereof are known in the art and can be used in various applications, including the fields of medicine and pharmaceuticals. For example, bioactive isonitrile-containing metabolites are being increasingly isolated and are considered among the best small-molecule leads for addressing the 300-500 million infections and 1-3 million deaths caused annually by malaria. The spread of resistant strains and the rise in global temperatures make this one of the highest priorities of the World Health Organization for the third world and North America.
Various methods for synthesizing isonitrile compounds are also known in the art. For example, it is known that isonitriles can be synthesized by the reaction of primary amines with dichlorocarbene or by dehydration of a formamide with phosphorus oxychloride. The Hofmann synthesis is a chemical test for primary amines based on their reaction with potassium hydroxide and chloroform as dichlorocarbene precursors to isonitriles. Another route to producing isonitriles is by reaction of organolithium compounds with oxazoles and benzoxazoles. A further synthetic route toward isonitriles includes condensation of an amine with formic acid to yield a formamide, and subsequent dehydration of this formamide. Phosgene can be used in combination with the formamide to yield isonitriles.
Isonitriles are used as reactants in multi-component Ugi and Passerini condensations, heterocycle synthesis, in radical and Pauson-Khand reactions and as ligands and in medical imaging.
There are disadvantages associated with the known methods of synthesizing isonitriles. The deprotonation-alkylation syntheses are limited to special substrates and conjugate additions with alkylisonitriles are rare, extremely challenging, and require additional activation through further conjugation. Further, alkyneisonitriles are virtually unknown except as components of interstellar gases and their reactivity remains relatively unexplored. The dearth of isonitrile-based methodology may be preventing direct, rapid access to bioactive isonitrile-containing carbocycles. Recourse to multi-step sequences is often required. For example, the synthesis of an anti-fouling isonitrile may require as many as ten steps to convert a ketone into an isonitrile.
The commercial availability of isonitriles is limited and those that are commercially available can be expensive.
Thus, there is a need in the art to develop new connectivity methods, access isonitriles having new structural diversity, reveal fundamental reactivity patterns in alkylations and conjugate additions, and establish the essential principles for performing transition metal catalysis with isonitriles. Furthermore, it would be advantageous if the isonitriles can be produced in a minimum number of steps, are cost effective to produce and result in high yields.